Study of the oxidation mechanisms associated to new dimeric and trimeric esters of ferulic acid

Accepted Manuscript Study of the oxidation mechanisms associated to new dimeric and trimeric esters of ferulic acid Roberto C. Guillén-Villar, Yamileth Vargas-Álvarez, Rubicelia Vargas, Jorge Garza, Myrna H. Matus, Magali Salas-Reyes, Zaira Domínguez PII: DOI: Reference:

S1572-6657(15)00004-1 http://dx.doi.org/10.1016/j.jelechem.2015.01.003 JEAC 1962

To appear in:

Journal of Electroanalytical Chemistry

Received Date: Revised Date: Accepted Date:

19 October 2014 24 December 2014 7 January 2015

Please cite this article as: R.C. Guillén-Villar, Y. Vargas-Álvarez, R. Vargas, J. Garza, M.H. Matus, M. Salas-Reyes, Z. Domínguez, Study of the oxidation mechanisms associated to new dimeric and trimeric esters of ferulic acid, Journal of Electroanalytical Chemistry (2015), doi: http://dx.doi.org/10.1016/j.jelechem.2015.01.003

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Study of the oxidation mechanisms associated to new dimeric and trimeric esters of ferulic acid Roberto C. Guillén-Villar,a Yamileth Vargas-Álvarez,a Rubicelia Vargas,b Jorge Garza,b Myrna H. Matus,a Magali Salas-Reyes,a,* and Zaira Domíngueza,* a

Unidad de Servicios de Apoyo en Resolución Analítica,

Universidad Veracruzana, A.P. 575, Xalapa, Ver., México b

Departamento de Química, División de Ciencias Básicas e Ingeniería,

Universidad Autónoma Metropolitana-Iztapalapa, A.P. 55-534, México, D.F., México

Abstract: The electrochemical behaviour of new ferulic acid derivatives, three dimeric and one tripodal esters as well as the monomeric benzylic ester, is described. All of them follow an ECE (electrochemical-chemical-electrochemical) oxidation mechanism. Electrografting processes were observed too, except in the case of the monomeric ester. Interestingly, topology seems to play an important role in their capacity of being adsorbed by the electrode, which suggest that a greater reactivity of the bi- and tri- radicals, probably generated during the first steps of electrochemical oxidation of this type of compounds or an increase of the van der Waals interactions between huge molecules and the electrode surface, could be the main responsible. In addition, electrodonating power, as that defined within the density functional theory, was estimated for the benzylic ester, one dimeric ester, the tripodal ester, and the ferulic acid. This quantity was compared with the corresponding experimental values of the oxidation potential. Results show that monomers are more effective for the process of donating electrons; however, a higher number of ferulic units increases the ability of the bis and tris structures to increase their electrodonating power. Keywords: Cyclic voltammetry, ferulic esters, electrografting, van der Waals interactions, vertical and adiabatic ionization potentials, electrodonating power. * Corresponding authors. Tel.: +52 22 88 41 89 17 E-mail addresses: [email protected] (Zaira Domínguez), [email protected] (Magali SalasReyes).

1

1. Introduction Phenolic compounds have attracted the attention of numerous research groups during the last years, since it is believed that they contribute to prevent the oxidative damage caused by free radicals and reactive oxygen species (ROS). [13] They belong to a huge family of compounds that include phenolic acids derived from benzoic or cinnamic acids and extend to flavonoids or tannins, all of them secondary metabolites ubiquitous in plants, [4] such as the bioactives caffeic acid (CA), sinapic acid (SA), and ferulic acid (FA), three members of hydroxycinnamic acids group (Figure 1). Figure 1 FA occurs in vegetables, some fruits, sweet corn, rice bran, and coffee, [5,6] and exhibits a wide range of therapeutic properties like neuroprotective, hepatoprotective, radioprotective, antidiabetes, antiapoptotic, antiageing, and antiinflamatory effects, which could be related to its antioxidant capacity. [5] FA dimeric derivatives are present in nature too, for example covalent diferulates cross-linked between polysaccharides (structure 1 in Figure 2) are found in plant tissues. [7] On the other hand, compounds 2 and 3 were found in Ficus foveolata, [8] which is employed to prepare a rejuvenating agent and a tonic to enhance the sexual performance by the people of the North and North-eastern part of Thailand. Compound 2 was also isolated from Pachycentria formosana, [9] an endemic creeping shrub from the forests of Taiwan, whereas a mixture of 4 and 5 was found in Stereospermum acuminatissimum, [10] a tall tree from the forest of west tropical Africa, whose leaves and barks are used for antiinflammatory purposes in the Cameroonian traditional medicine. Another symmetrical derivative that contains two ferulyl moieties into its structure is the curcumine (diferuloylmethane, compound 6 in Figure 2), the principal component of turmeric, one of the most important ingredients in curry powder, [11] which has received the attention of numerous research groups due to their high medicinal potential, probably associated to its antioxidant capacity. [12-16]

2

Figure 2 The interesting therapeutic properties of FA have motivated the design of new synthetic derivatives of this hydroxycinnamic acid, [17-19] in order to understand the structure-activity relationship and to enhance its beneficial contributions to human health. On the other hand, electrochemistry has become an important tool in the study of antioxidant properties of organic compounds, [17,18,20,21] since their oxidation potentials can be used to study its electron donating capacity, and also as an indicator of its radical scavenging ability. It has been shown that there is a relationship between less positive oxidation potential (or a higher susceptibility to electrochemical oxidation) and higher radical scavenging activities. [17,18,21] Electrochemical behaviour of FA has been described extensively in the literature, [22-25] nevertheless the interest in the study of electrochemical oxidation of new derivatives of this acid still continues. Recently, we have undertaken the study of the oxidation mechanisms of new

hydroxycinnamic

acid

derivatives

with

dimeric

topology

through

electrochemical and theoretical chemistry methods. Our interest in this type of compounds arise from the fact that similar structures are found in natural products with medicinal potential, and even synthetic analogues have been prepared in order to explore their therapeutic properties. [26,27] In a previous report, [28] we found that the electrochemical oxidation in aprotic medium of three symmetrical bis-amides derived from FA involves the lost of an electron followed by a deprotonation reaction, and the subsequent delocalization of the radical toward the carbon α to the carbonyl group, at the lateral chain of ferulyl moieties, which react in a very efficient way with the surface of the glassy carbon electrode (GCE). Theoretical calculations and electrochemical experiments confirmed the proposed mechanism. Although adsorption phenomena were observed previously by our group in monomeric ferulic amides too, [25] dimeric topology seems to increase the blocking effect of the electrode surface in a significant way. In contrast, during the electrochemical oxidation of analogous CA amides, similar electrografting processes were not observed. [29] In addition, we found interesting differences in 3

the electrochemical behaviour of dimeric ester derivatives and amide derivatives of CA, nevertheless that all of them contained two caffeoyl electroactive moieties, which suggests that small differences in the structure result in interesting changes in the electrochemical responses of this type of compounds. In the present work, we report the electrochemical oxidation in aprotic medium of new three dimeric esters 7-9 derived from FA (Figure 3). Cyclic voltammetry of analogous CA dimeric esters was carried out in DMSO by our group before. [29] In order to compare the effect of the topology in the electrochemical behaviour of 7-9, the anodic oxidation of monomeric benzylic ester of FA, compound 10, is also discussed here. On the other hand, inspired by Leontopodic acid (a natural triester derived from CA with interesting antioxidant and protective DNA properties), [30] we prepared the new tripodal ester 11, whose conformational preferences were previously analyzed in silico by our group. [31] Its electrochemical behaviour is also presented here through cyclic voltammetry results. In addition, Density Functional Theory (DFT) calculations of compounds 7, 10, 11, as well FA, were performed in order to evaluate the electrodonating power (ω–), as described by Gázquez et al., [32] therefore, we have estimated the corresponding ionization potentials (IP), adiabatic and vertical, in gas phase and applying solvent effect. Comparison of the obtained theoretical (IP and ω–) and experimental (oxidation potential) trends is discussed, as well. Figure 3 2. Experimental 2.1 Instrumentation Melting points were determined with Melt-Temp apparatus and are not corrected. 1H and Technologies

13

C spectra were recorded on a JEOL GSX-270 and an Agilent

400/54

Premium Shielded

spectrometers,

using

deuterated

chloroform (CDCl3) or acetone (C3D6O) as solvents. Chemical shifts were recorded in δ (ppm) values downfield from TMS as internal standard. Coupling constants (J) are given in Hertz. HR-ESI-TOF MS spectra were measured on a Gi969A Agilent 4

spectrometer. Cyclic voltammetry experiments were performed in a potentiostat PGZ-301

(Radiometer

Copenhagen)

with

positive

feedback

resistance

compensation. 2.2 Chemicals Ferulic acid (99%), 1,2-dibromoethane (98%), 1,5-dibromopentane (97%), 1,8-dibromooctane (98%), 1,3,5-tris(bromomethyl)benzene (97%), benzyl bromide (98

%),

tetrabutylammonium

hydroxide

in

methanol

(1.0

M)

and

tetrabutylammonium hexafluorophosphate 98% (n-Bu4NP6) were purchased from Sigma-Aldrich and were used without purification. Acetonitrile (AN) (content of H2O <0.1%, CROMASOLV ® Plus) was used as solvent in the preparation of compounds 7-9 and 11 and during the electrochemical experiments too. Dimethylformamide (DMF) reagent grade, was employed in the synthesis of compound 10 after distilation. Products were purified by flash column chromatography on silica gel 230-400 mesh using as eluent mixtures of EtOAc/hexanes. 2.3 Synthesis Procedure to obtain 7-9 and 11. In a 250 mL flask provided with a stir bar, were placed: 5.21mmol (1.01 g) of FA, 50 mL of AN, and 5.14 mmol (5.2mL) of a solution 1 M of tetrabutylammonium hydroxide in methanol. The resulting mixture was allowed to stir for 30 minutes at room temperature, after that, 2.50 or 1.70 mmol (in the case of 7-9 or 11, respectively) of the corresponding halide were added directly to the solution. The reactions proceeded at room temperature for 52 h, after which the crude of reaction was dried under vacuum. Then 50 mL of CH2Cl2 were added, the solution was washed several times with water and the organic layer was dried over magnesium sulfate. The solvent was removed in a rotary evaporator and the residue was chromatographed on silica gel. Yields are given for isolated products. Compound 10 was prepared in agreement to the procedure reported by Son et al. [33] 5

Benzylic ester of ferulic acid (10) The product was a pale yellow liquid. Isolated yield: 40%.1H NMR (270 MHz, CDCl3) δ (ppm): 3.92 (s, 3H), 5.25 (s, 2H), 5.93 (s, OH), 6.32 (d, 3JHH=16.0 Hz, 1H), 6.90 (d, 3JHH=8.0 Hz, 1H), 7.02 (d, 4JHH=2.0 Hz, 1H), 7.06 (dd, 3JHH=8.0 Hz, 4

JHH=2.0, 1H), 7.34-7.43 (m, 5H). 7.64 (d, 3JHH=16.0 Hz,1H), 13C NMR (100.5 MHz,

CDCl3) δ (ppm): 56.0, 63.3, 109.3, 114.8, 115.2, 123.2, 127.0, 128.3, 128.4, 128.7, 136.2, 145.3, 146.8, 148.1, 167.2 1,2-di-O-feruloylethanediol (7) M.p. 103 ºC. Isolated yield: 15%.1H NMR (400 MHz, (CD3)2CO) δ (ppm): 3.91 (s, 6H), 4.44 (s, 4H), 6.43 (d, 3JHH=15.9 Hz, 2H), 6.87 (d, 3JHH=8.1 Hz, 2H), 7.15 (dd, 3

JHH=8.1 Hz, 3JHH=2.0 Hz, 2H), 7.36 (d, 4JHH=2.0 Hz, 2H), 7.64 (d, 3JHH=16.0 Hz,

2H), 8.15 (broad signal, 2H, OH).

13

C NMR (100.5 MHz, CDCl3) δ (ppm): 56.3,

62.5, 111.3, 115.3, 116.0, 124.2, 127.4, 146.2, 148.8, 150.2, 167.4. MS (ESI-TOF) calculated for [C22H22O8Na]+ 437.1212, found [M + Na]+ 437.1207 1,5-di-O-feruloylpentanediol (8) M.p. 126 ºC. Isolated yield: 15%. 1H NMR (270 MHz, CDCl3) δ (ppm): 1.52 (m, 2H), 1.75 (m, 4H), 3.91 (s, 6H), 4.22 (t, 3JHH=6.6 Hz, 4H), 5.89 (s, 2H, OH), 6.27 (d, 3

JHH=16.0 Hz, 2H,), 6.89 (d, 3JHH=8.0 Hz, 2H), 7.02 (d, 4JHH=2.0 Hz, 2H), 7.05 (dd,

3

JHH=8.0 Hz, 3JHH=2.0 Hz, 2H), 7.60 (d, 3JHH=16.0 Hz, 2H).

13

C NMR (100.5 MHz,

CDCl3) δ (ppm): 22.7, 28.5, 56.0, 64.3, 109.3, 114.7, 115.5, 123.1, 127.0, 144.9, 146.8, 148.0, 167.4.MS (ESI-TOF) calculated for [C25H29O8]+ 457.1852, found [M + Na]+ 457.1850 1,8-di-O-feruloyloctanediol (9) M.p. 94 ºC. Isolated yield: 13%. 1H NMR (270 MHz, CDCl3) δ (ppm): 1.36 (m, 8H), 1.68 (m, 4H), 3.90 (s, 6H), 4.17 (t, 3JHH=6.7 Hz, 4H), 5.90 (s, 2H, OH), 6.24 (d, 3

JHH=16.0 Hz, 2H), 6.88 (d, 3JHH= 8.0 Hz, 2H), 7.01 (d, 4JHH=2.0 Hz, 2H), 7.05 (dd,

3

JHH=8.0, 4JHH=2.0 Hz, 2H), 7.56 (d, 3JHH=16.0 Hz, 2H).

6

13

C NMR (100.5 MHz,

CDCl3) δ (ppm): 25.9, 28.8, 29.2, 56.0, 64.6, 109.3, 114.7, 115.6, 123.1, 127.0, 144.7, 146.8, 148.0, 167.4. MS (ESI-TOF) calculated for [C28H35O8]+ 499.2332, found [M + H]+ 499.2329 1,3,5-tri-O-(feruloyl)benzenetrimethanol (11) M.p. 101ºC. Isolated yield: 25.43%. 1H NMR (400 MHz, ((CD3)2CO) δ (ppm): 3.88 (s, 9H), 5.25 (s, 6H), 6.45 (d, 3JHH=15.8 Hz, 3H), 6.84 (d, 3JHH=8.0 Hz, 3H), 7.12 (dd, 3JHH=8.0 Hz, 3JHH=1.9 Hz, 3H), 7.32 (d, 4JHH=1.9 Hz, 3H), 7.49 (s, 3H), 7.63 (d, 3

JHH=15.8 Hz, 3H), 8.15 (broad signal, 3H, OH).

13

C NMR (100.5 MHz, ((CD3)2CO)

δ (ppm): 56.3, 66.0, 111.3, 115.5, 116.0, 124.1, 127.4, 128.3, 138.5, 146.2, 148.7, 150.2, 167.3. MS (ESI-TOF) calculated for [C39H37O12]+ 697.2285, found [M + H]+ 697.2278

2.4 Voltammetry Experiments A Pyrex glass three-electrode cell was used in the electrochemical experiments. The working electrode was a 3 mm diameter glassy carbon disk (Sigradur G from HTW, Germany). This electrode was polished with 1 µm alumina powder and rinsed in ultrasound bath with distilled water and ethanol before each run. A platinum mesh was used as counter electrode and a saturated calomel electrode (SCE) as reference. The reference electrode was connected to the cell through a salt bridge containing the same supporting electrolyte concentration as the working solution. All electrochemical experiments were performed at 25 °C under a high purity nitrogen atmosphere. 3. Theoretical Study We estimated for compounds 7, 10, 11, and FA the electrodonating (ω–) and electroaccepting (ω+) powers. [32] These reactivity indexes were developed within the DFT framework in order to analyze charge transfer processes (including partial charge transfer) and they are designed to account for the capacity of the system to 7

donate or accept electronic charge. In that way, low values of ω– indicates an effective electrodonating capacity, whereas high values of ω+ indicates an effective electroaccepting capacity. The electrodonating capacity of a system can be obtained through the chemical potential, µ–, which considers the energy change during an electronic donating process (i.e., from N to N–1 electrons) and was found to be: ଵ

ߤି = − ସ ሺ3‫ ܫ‬+ ‫ܣ‬ሻ

(1)

and the hardness, η: ଵ

(2)

ߟ = ଶ ሺ‫ ܫ‬− ‫ ܣ‬ሻ

Thus, the electrodonating power can be easily calculated with the vertical ionization energy (IP) and electron affinity (EA):

ωି ≡

ሺఓ ష ሻమ ଶఎ

ሺଷூା஺ሻ మ

(3)

= ଵ଺ሺூି஺ሻ

Similarly, the electroaccepting capacity of a system can be obtained through the chemical potential, µ+, which considers the energy change during an electronic accepting process (i.e., from N to N+1 electrons): ଵ

ߤା = − ସ ሺ‫ ܫ‬+ 3‫ܣ‬ሻ

(4)

and the hardness, η:

ωା ≡

൫ఓ శ ൯ ଶఎ

మ

ሺூାଷ஺ሻమ

(5)

= ଵ଺ሺூି஺ሻ

In this study, the electron donation process is key, since we are evaluating the antioxidant ability of the different compounds. Thus, in order to get an appropriate comparison with the cyclic voltammetry experiments, our calculations are centred on the IP as well as on ω– (the corresponding EAs were also obtained as well as ω+, see the Supporting Information). 8

Optimization calculations were performed employing the TeraChem [34] program at a DFT level with the PBE0 functional [35] and the 6-311G** basis set. [36] Optimizations were followed by frequency calculations in order to ensure energy minima. For compound 7, PM3 geometries were the starting point for the optimization process employing Gaussian 09 software; [37] previous optimization with a semi-empirical method such as PM3 was necessary because of the several dihedral angles involved in the molecule. On the other hand, the PBE0/6-311G** optimization of compound 11 was obtained starting from an already optimized structure at the B3LYP/DGDZVP2 level of calculation. [31] As we have mention, the AN was used as solvent for the cyclic voltammetry experiments, for this reason we have employed the implicit solvent model, in order to incorporate this effect, through the SMD [38] approach. Thus, single point calculations with this approach were obtained by using the Gaussian 09 program (see Tables S1 and S2 in Supporting Information). 4. Results and Discussion 4.1 Electrochemical study of the oxidation process of 7-10 First, we will discuss the results obtained for the electrochemical oxidation of compounds 7-10. Due to the low solubility of 7 in AN, we employed a solution 1 mmol·L-1 to perform the cyclic voltammetry experiment of this compound, whereas twofold concentrated solutions were used in the case of 8-10. On the other hand, since electrochemical response of 9 was very similar to that of 8, the corresponding graphic is shown in the Supporting Information (Figure S1). Figure 4 The electrochemical behaviour of compounds 7-10 in AN showed a typical oxidation wave (I) and a broadened reduction wave (II) in the reverse scan, as it can be observed from voltammograms of 7,8, and 10 shown in Figure 4. These electrochemical responses are characteristic of FA, CA, and their electroactive moieties, guaiacol and cathecol, respectively, [25] but also of hydroquinone, an isomer of cathecol.[39] An electrochemical-chemical-electrochemical (ECE) 9

mechanism has been proposed to explain the electrochemical behaviour of this type of compounds, which involves the lost of one electron followed by a fast deprotonation reaction and, finally, the lost of a second electron from the systems, such as is shown in Scheme 1. [24] The peak intensity registered in the case of compound 10 is practically the same reported before by our group for caffeic acid phenethyl ester [25] (I/µA was 90) employing the same experimental conditions (scan rate and concentration), whose bielectronic nature of the oxidative process was confirmed by coulometry. Taking this into account, we can deduce that electron stoichiometry is also two in the case of 10 (I/µA = 100), whereas around four electrons must be involved in the electrochemical oxidation of dimeric compounds (I/µA were 73 and 136 employing 1 and 2 mmol L-1 solutions of 7 and 8, respectively). The decrement in the observed current peak for 7 and 8, could be explained from the fact that both compounds are heavier with respect to caffeic acid phenethyl ester, and it is known that the intensity of the current peak is related to the diffusion coefficient, which depends on the molecular weight. [40,41] An estimation of the decrement in the intensity current peak of compound 7 with respect to compound 10 was evaluated by calculating the theoretical intensity of the current peak (ip) for each case using the Randles-Sevcik equation: [40] ip = (2.69 x 105)n3/2A D1/2Cν1/2

(6)

where n is the number of transferred electrons (considered 4 and 2 in the case of compound 7 and 10, respectively), A is the electrode surface (cm2), D is the diffusion coefficient (cm2/s), C is the concentration (mol/cm3), and ν is the scan rate (V s−1). The diffusion coefficient of both compounds was estimated according to the following equation: [41] DAN = (35.2 ± 0.05 x 10-6) – (6.59 ± 0.23 x 10-8)·MW

10

(7)

where MW is the molecular weight. From these equations, a calculated decrement of 30% was obtained, whereas the experimental decrement was of 28%. This approach allows us to confirm that four electrons are involved during the electrochemical oxidation of compound 7. Scheme 1 It should be noted from Figure 4, that the peak potential I for monomeric ester 10 appears at 1.22 V vs SCE. A shifting to more anodic values is observed for the oxidation peaks of dimeric compounds: 1.27 and 1.38 V vs SCE for the case of 7 and 8, respectively, whereas a potential of 1.41 V vs SCE was registered for 9, which shows that a relationship between this parameter and the length of the alkyl connector exists. In addition, after four oxidation cycles the electrochemical response for compound 9 disappears almost completely, whereas in the case of compounds 7 and 8 ten and six cycles, respectively (Figure 5), were necessary. This fact can be attributed to an electrografting process, since the voltammograms of 7-9 are recovered only if the electrode surface is polished. In contrast, after twenty five experiments, the electrochemical response of compound 10 remains practically without changes. We have informed before about the chemical adsorption of monomeric amides derived from FA on the GCE surface, [25] which occurs during electrochemical experiments, phenomenon that results magnified in the case of the dimeric analogous amides (where passivation of the electrode occurs after the second or third cycle). [28] However, it is interesting the fact that compounds 7-9 block the surface of the electrode showing a clear tendency between length of the alkyl connector and the necessary number of cycles for the complete loss of electrochemical response. On the other hand, monomeric derivative does not react with the GCE. From these facts, it is clear, also in the case of the esters reported here, that dimeric topology favours the chemical adsorption of ferulic derivatives on the surface of the electrode. Figure 5

11

During the electrochemical oxidation of FA derivatives, radical I shown in Scheme 2 could be generated. [28]Error! Bookmark not defined. Spin density calculations performed by our group suggested that the unpaired electron is found mainly in the carbon labelled as 2 (C2), followed by the ipso carbon 4 (C4), and oxygen 11 (O11). Taking into account the connection between the spin density and the local reactivity criteria provided by the Fukui function, one can predict that the same sites could react with the electrode surface during the electrochemical experiment of 7-9. Nevertheless, it is not clear how dimeric topology contribute to the reactivity of these three compounds toward GCE, whereas monomeric ester 10 seems unreactive under the same experimental conditions. A greater reactivity of biradicals probably generated during the first steps of electrochemical oxidation of 7-9, with respect to the monoradical produced from compound 10, could explain at least in part the observed behaviour. A relationship between molecular size (9>8>7>10) seems also be implied in the increment of the attractive interaction forces between GCE surface and FA derivatives studied by our group. Scheme 2 On the other hand, the voltammogram of the blocked electrode with compound 9 is shown in Figure 6. Before the experiment, the modified electrode was cleaned in an ultrasonic bath, employing different solvents, and transferred to a fresh solution of Bu4NPF6 0.1 M. As it can be observed, a peak at -0.18 V vs SCE and a small broad wave at 0.04 V vs SCE were registered at cathodic and anodic potentials, respectively. This fact is consistent with the presence of an electroactive species on the blocked GCE surface. Taking into account the results of the spin density calculations described above, and previous reports dealing with the electrochemical oxidation of ferulic and coumaric acids, [24] where spectroscopic analysis of the oxidation products permitted to the authors the identification of dimeric compounds that arise from radical I, shown in scheme 2 (where the site of reaction was C2), we proposed that α,β unsaturated cyclic ketone moieties are bonded to the GCE surface (such as structure II shown in Scheme 2). 12

This type of chemical species has a structure similar to the quinomethides (QMs), which are reactive intermediates in lignins transformations. Dimmel et al., [42] have reported the electrochemical responses of QMs in mixtures of solvents, such as DMSO-chloroform and AN-chloroform, however, they found that small changes in QMs structure provoke important changes in the reduction potential, complicating direct comparisons between the values of the reduction potential observed for this kind of compounds. The same group has reported that nucleophilic solvents, and even traces of water, can affect to QMs. Although few quinomethides are stable enough to be analysed electrochemically, Evans was able to obtain a QM stabilized by hindered substituents close to the ketone group, through the oxidation of the corresponding phenoxide. [43] Interestingly, in the same work, he reported the electrochemical oxidation of the 2,6-di-tert-butyl-4(2propenyl)phenoxide, and observed that during the experiment the corresponding dimeric QM is obtained as the product (see Figure S2 in Supporting Information). This result supports the fact that the unpaired electron of radical I (Scheme 2) is mainly located at C2, and that it is the more reactive species in this type of phenolic derivatives, such as Petrucci has informed, [24] and our theoretical calculation have predicted. [28] Figure 6 On the other hand, the calculated charge, associated to the reduction wave observed in the voltammogram of the modified electrode with compound 9 was 69 µC cm-2 (geometric area), whereas the surface concentration was 3.58 × 10-10 mol cm-2, which corresponds to a monolayer coating. [39,40,44-46] Since, during a second cycle, the voltammetric peaks disappears, we can conclude that a desorption process is occurring also at cathodic potentials. In addition, the peak observed at 0.04 V vs SCE could be assigned to the electrochemical oxidation of the corresponding phenoxide ion, generated during the desorption process. [23] Electrochemical responses of compounds 8 and 9 were also recorded employing different scan rates (from 0.025 V/s to 0.5 V/s). Only in the case of compound 9, the oxidation peak became in a broad wave followed by a narrow 13

peak observed around 1.33 and 1.47 V vs SCE, respectively, at the lower scan rate (see Figure S3 in the Supporting Information). This behaviour could be consistent with the coexistence of the two electrochemical processes occurring during the experiment, such as has been described above: the electrografting and the ECE oxidation. 4.2 Electrochemical behaviour of compound 11 Cyclic voltammetry of the oxidation process of tripodal compound 11 was performed employing a 1 mmol·L-1 solution, since as in the case of the dimeric ester 7, the tripodal compound shows low solubility in AN. Voltammogram of 11 is presented in Figure 7, which shows two broad anodic peaks at 1.27(I) and 1.53(II) V vs SCE, respectively, whereas a slight and broad reduction wave (III) appears around 0.63 V vs SCE. Figure 7 A comparison between Figures 4 and 7 makes evident the difference in the electrochemical behaviour of dimeric and tripodal esters. In fact, voltammogram of compound 11 resembles the corresponding graphs of two dimeric amides derived from FA, previously reported by our group, which had m-xylylendiamine or 1,3phenylendiamine as connectors of the ferulyl moieties. [28] The registered values for the peaks I and II of the tripodal compound are also very close to the corresponding values of the dimeric amides (1.20 and 1.29 V vs SCE for peak I, and 1.54 and 1.59 V vs SCE for peak II). In both symmetrical amides, we found that wave I corresponded to a prewave, which is characteristic of an electrochemical process where a product of oxidation is strongly adsorbed, whereas peak II could be the corresponding diffusion controlled wave. Taking this into account, we performed several electrochemical experiments with the solution of compound 11, which are described as follows. After cycling the electrode potential between the initial potential and the foot of the second wave, we observed that wave I was completely suppressed, as shown in Figure 8. The covalent bonding of the tripodal compound with the 14

electrode can be deduced since the electrochemical response is recovered at this point only after an electrode surface polished procedure. In addition, after the electrografting process, the electrode was rinsed several times with acetone, followed by sonication in pure AN, and then transferred to a cell containing only the solution of supporting electrolyte, however no peak was registered during the electrochemical reduction of the modified electrode. On the other hand, we found a linear relationship between the anodic peak current of peak I and the scan rate of compound 11 (see Figure S4 in the Supporting Information). These results confirm that this peak is a prewave, related to an adsorption phenomenon. It should be mentioned that after each experiment the GCE surface was carefully polished. Figure 8 From these observations, we can conclude that the connector between feruloyl moieties, topology and molecular size, could play important roles in the very efficient electrografting processes which are characteristic of this type of compounds. An increase in the van der Waals interactions between huge molecules and the GCE surface seems to be the further cause of the strong capacity of dimeric and tripodal FA derivatives to block the electrode, as well as the reactivity of radical I (Scheme 2), toward the electrode during the experiment, since similar processes have been not observed with dimeric CA analogous. [29]Error! Bookmark not defined. The importance of van der Waals interactions in the electrografting processes observed in this type of compounds is currently under investigation in our group. 4.3 Theoretical geometries for FA and compounds 7, 10 and 11 FA and compound 10 structures are shown in Figure 9. With the method employed in this work, both structures present a planar Cs symmetry. Figure 9 For compound 7, PM3 optimization produced nine different conformers within a relative energy of 8.65 kcal/mol. They were all used as initial geometries at 15

the PBE0/6-311G** level of calculation. As a result, five lowest energy structures were used in this work taking into account a relative energy of 2.43 kcal/mol or less. In Figure 10A we can see that conformer 7-1 (the one with the lowest energy) presents a planar geometry with C2h symmetry. Conformer 7-2 (Figure 10B) presents a C2 symmetry which differs from 7-1 because of the O-C-C=C dihedral angles starting from the oxygen of the ester functional groups, which are 180° for 7-1 and 0° for 7-2. In conformer 7-3 (Figure 10C), C2 symmetry is present and the O-C-C-O dihedral angle corresponding to the connection between both FA units is of 69°, producing a bending with respect to the planar conformer 7-1; in addition, there is a slight difference, 0° for 7-1 and 1.09° for 7-3, at the O-C-C=C dihedral angle related to the carboxylic units. Conformer 7-4 (Figure 10D) also shows C2 symmetry and a difference of 180° with respect to 7-1 on the O-C-C=C dihedral angle. Finally, conformer 7-5 (Figure 10E) presents a C1 symmetry and a 90° central O-C-C-O dihedral angle corresponding to the connection between FA units, with respect to 0° for 7-1. Figure 10 Optimized geometry for compound 11 is shown in Figure 11. In this case, even though C3v symmetry is known to be present, no symmetry constraints were applied during the optimization process. From the optimized structure, this conformer exhibits three possible different hydrogen bonds, with H···O distances of 2.79 Å, 2.56 Å, and 2.54 Å (see a, b, and c, respectively, in Figure 11). Although these distances are within the range of weak hydrogen bonds, [47] we have checked such interactions by using the atoms in molecules (AIM) analysis. [48] From this analysis we found just one kind of hydrogen bond. The graphic molecular description, obtained by a code based on GPUs, [49] of this conformer is depicted in Figure 12. In this picture, the small spheres represent points where the gradient of the electron density is cancelled (critical points), and the lines connect these points with the corresponding attractors (nuclei). From this figure, clearly we see just one type of hydrogen bond, which is indicated by the arrows in this figure. Evidently, the hydrogen bonds involved in this structure do not contribute to its 16

stabilization and, consequently, the non-planarity exhibited by this molecule is not induced by hydrogen bonds. This result is interesting because we tried to obtain the planar molecule, with PM3 and B3LYP models, starting from a planar geometry and we always recovered a folded system, even when C3v symmetry was imposed. We mention this observation on the structure and the corresponding explanation requires a deep analysis, which is out of the scope of this work since it is not a determinant result for the discussion. Figure 11 Figure 12 4.4 Ionization potentials and ω– of FA and compounds 7, 10, and 11 It is important to note that even though the experimental behaviour analysed in this work corresponds to an ECE mechanism, the initial step of this mechanism corresponds to a simple electronic transfer (SET). It has been theoretically demonstrated that once the first electron is detached from the oxygen of the system, [50] the following deprotonation is energetically favourable, which is in agreement with a fast deprotonation as experimentally proposed. In addition, lost of a second electron is already favourable, since the resulting system from the first two steps is a radical. Thus, we are focusing in the first electron donation in this work as described next. The optimized structures were used to estimate the vertical IP as well as the EA (Table S1 in the Supporting Information) in order to obtain the reactivity index, ω–, which lead to determine the antioxidant capacity of compounds 7, 10, 11, and FA taking into account a SET. In the case of compound 7, where several conformers were found within 5 kcal/mol of variation in energy, the vertical IPs and EAs were calculated as well as the ω–, since differences of less than 0.08 eV were obtained for the latter (see Table S1 of the Supporting Information), the average values from all conformers were used. 17

Table 1 shows the comparison between the calculated vertical and adiabatic potential energies as well as the electrodonating power (using AN as solvent) and the experimental oxidation potential for compounds 7, 10, 11, and FA. Table 1 Comparison between compounds 7 and 11 show that there is a difference of 0.21 eV for ω−. Since low values of ω– indicate an effective electrodonating capacity, it can be said that the electronic structure of the bis derivate presents a better capacity to donate electrons than the tris derivate. Comparing with the corresponding monomer derivate, compound 10, an even lower value is obtained by 0.58 and 0.79 eV of difference with respect to compounds 7 and 11, respectively. In the case of FA, there is a higher value by 0.11 eV with respect to compound 10. These results show that monomeric structures are more prone to donate electrons than the bis or tris structures. Thus, the observed trend for ω− is 10
the error bars in calculations, it can be said that FA and 10 are very similar with respect to their antioxidant capacity and, it can be stated that the correct order for the antioxidant capacity is as follows: FA≈10>7>11. It also can be said that monomers FA and 10 are better antioxidants than the corresponding dimer, 7, and trimer, 11, when only one electron is donated from the molecular system. 5. Conclusions The electrochemical behaviour of a series of new FA derivatives was reported here: three dimeric and one tripodal esters, as well as the monomeric benzylic ester. Although all of them follow an ECE (electrochemical-chemicalelectrochemical) oxidation mechanism, characteristic of CA and FA derivatives, electrografting processes were observed too, except in the case of the monomeric ester. Interestingly, topology seems to play an important role in the effectiveness of the chemical adsorption phenomena, suggesting that a greater reactivity of the bior tri- radicals, probably generated during the first steps of electrochemical oxidation of this type of compounds, could be the responsible of their reactivity toward the GCE surface. On the other hand, a relationship between molecular size could also be implied in the increment of the attractive interaction forces between GCE surface and FA derivatives. In this case, the van der Waals interactions could be implied, which is under study in our group. On the other hand, the theoretical findings in this work present a general behaviour of esters derived from FA with respect to a SET. Comparison of calculated values applying solvent effect (with AN as solvent) for the donation of one electron and experimental values suggest that the electrodonating power, ω–, is a good reactivity index. In general, ω– and OP values indicate that monomers, FA and 10, have a better performance as antioxidants with respect to the dimer and the trimer. Optimization results show that planar geometry of the monomers could play an important role in the antioxidant capacity, since dimers and trimers structures present intramolecular folding due to the presence of hydrogen bonds. However, the presence of more ferulic units in the molecular structure may lead to

19

the ability of donating more than one electron. A further study with diradicals and triradicals is necessary for a better understanding of the SET in dimers and trimers. Acknowledgments This work was supported by CONACyT-Mexico through grants 134275, 169409, 154784, and 155070, COVECyT-Mexico FOMIX VER-2009-C03-127523, and PROMEP/103.5/12/2181. R.C.G.V. thanks also to CONACyT-Mexico for a Master scholarship, No. 350281. The authors gratefully acknowledge Dr. Felipe González (Departamento de Química, CINVESTAV) for the facilities provided to obtain the mass spectroscopy data of the compounds reported in this work and the spectra recorded on theJEOL GSX-270 NMR spectrometer. We also thank to the Laboratorio de Supercómputo y Visualización en Paralelo at the Universidad Autónoma Metropolitana-Iztapalapa. Supporting Information Available: Cyclic voltammetry of compound 9 in AN. Cyclic voltammetry of compound 9 at different scan rates. Cyclic voltammetry of compound 11 at different scan rates. Gas phase and solvent effect results for IPs, EAs, and electrodonating, ω-, and electroaccepting powers, ω+, for compounds 7, 10, 11, and FA. References [1] J. Martínez, J.J. Moreno, Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production, Biochem. Pharmacol. 59 (2000) 865-870. [2] R.W. Owen, A. Giacosa, W.E. Hull, R. Haubner, B. Spiegelhalder, H. Bartsch, The antioxidant/anticancer potential of phenolic compounds isolated from olive oil, Eur. J. Cancer 36 (2000) 1235-1247. [3] J.A.G. Crispo, D.R. Ansell, M. Piche, J.K. Eibl, N. Khaper, G.M. Ross, T.C. Tai, Protective effects of polyphenolic compounds on oxidative stress-induced cytotoxicity in PC12 cells, Can. J. Physiol. Pharmacol. 88 (2010) 429-438. [4] A. Soto-Vaca, A. Gutiérrez, J.N. Losso, Z. Xu, J.W. Finley, Evolution of phenolic compounds from color and flavor problems to health benefits, J. Agric. Food Chem. 60 (2012) 6658-6677. [5] M. Srinivasan, A.R. Sudheer, V.P. Menon, Ferulic acid: Therapeutic potential through its antioxidant property, J. Clin. Biochem. Nutr. 40 (2007) 92-100.

20

[6] Z. Zhao, M.H. Moghadasian, Chemistry, natural sources, dietary intake and pharmacokinetic properties of ferulic acid: A review, Food Chem. 109 (2008) 691702. [7] T. Ishii, Structure and functions of feruloylated polysaccharides, Plant Science 127 (1997) 111-127. [8] T. Sermboonpaisarn, P. Sawasdee, Potent and selective butyrylcholinesterase inhibitors from Ficus foveolata, Fitoterapia 83 (2012) 780-784. [9] J.-Y. Cho, T.-H. Lee, T.L. Hwang, S-Z. Yang, I.-S. Chen, T.-H. Chou, P.-J. Sung, J.-J. Chen, A new ferulic acid ester, a new ellagic acid derivative, and other constituents from Pachycentria formosana: Effects on neutrophil pro-inflammatory responses, Chem. Biodiversity 8 (2011) 1709-1716. [10] S.V.T. Sob, H.K. Wabo, C.-P. Tang, P. Tane, B.T. Ngadjui, Y. Ye, Phenol esters and other constituents from the stem barks of Stereospermum acuminatissimum, J. Asian Nat. Prod. Research 13(12) (2011) 1128-1134. [11] B.B. Aggarwal, C. Sundaram, N. Malani, H. Ichikawa, Curcumin: The Indian solid gold, Adv. Exp. Med. Biol., 595 (2007) 1–75. [12] B.B. Aggarwal, K.B. Harikumar, Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases, J. Biochem Cell Biol. 41 (2009) 40-59. [13] R.A. Sharma, S.A. Euden, S.I. Platton, D.N. Cooke, A. Shafayat, H.R. Hewitt, T.H. Markzylo, B. Morgan, D. Hemingway, S.M. Plummer, M. Pirmohamed, A.J. Gescher, W.P. Steward, Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res. 10(20) (2004) 6847-6854. [14] P.R. Holt, S. Katz, R. Kirshoff, Curcumin therapy in inflammatory bowel disease: a pilot study, Dig. Dis. Sci. 50 (2005) 2191-2193. [15] T. Hamagushi, K. Ono, M. Yamada, REVIEW: curcumine and Alzheimer´s disease, CNS Neurosci. Ther. 16 (2010) 285-297. [16] S. Rajput, M. Mandal, Antitumor promoting potential of selected phytochemicals derived from spices: a review, Eur. J. Cancer Prev. 21 (2012) 205215. [17] A. Gaspar, E.M. Garrido, M. Esteves, E. Quezada, N. Milhazes, J. Garrido, F. Borges, Hydroxycinnamic acid antioxidants: An electrochemical overview, Eur. J. Med. Chem. 44 (2009) 2092-2099. [18] F.M. Roleira, C. Siquet, E. Orrù, E.M. Garrido, J. Garrido, N. Milhazes, G. Podda, F. Paiva-Martins, S. Reis, R.A. Carvalho, E.J. Tavares da Silva, F. Borges, Lipophilic phenolic antioxidants: Correlation between antioxidant profile, partition coefficients and redox properties, Bioor. Med. Chem. 18 (2010) 5816-5825. [19] A. Murakami, Y. Namamura, K. Koshimizu, D. Takahashi, M. Matsumoto, K. Hagihara, H. Taniguchi, N. Eisaku, A. Hosoda, T. Tsuno, Y. Maruta, H. Won Kim, K. Kawabata, H. Ohigashi, FA15 a hydrophobic derivative of ferulic acid, suppresses inflammatory responses and skin tumor promotion: comparison with ferulic acid, Cancer Lett. 180 (2002) 121-129. [20] A. Masek, E. Chrzescijanska, M. Zaborski, Characteristics of curcumin using voltammetry, UV-vis, fluorescence and thermogravimetric analysis, Electrochim. Acta 107 (2013) 441-447. 21

[21] H. Hotta, S. Nagano, M. Ueda, Y. Tsujino, J. Koyama, T. Osaki, Higher radical scavenging activities of polyphenolic antioxidants can be ascribed to chemical reactions following their oxidation, Biochimi. Biophys. Acta 1572 (2002) 123-132. [22] S. K. Trabelsi, N. B. Tahar, B. Trabelsi, R. Abdelhedi, Electrochemical oxidation of ferulic acid in aqueous solutions at gold oxide and lead dioxide electrodes, J. Appl. Electrochem. 35 (2005) 967-973. [23] P. Hapiot, A. Neudeck, J. Pinson, H. Fulcrand, P. Neta, C. Rolando, Oxidation of caffeic acid and related hydroxycinnamic acids, J. Electroanal. Chem. 405 (1996) 169-176. [24] R. Petrucci, P. Astolfi, L. Greci, O. Firuzi, L. Saso, G. Marrosu, A spectroelectrochemical and chemical study on oxidation of hydroxycinnamic acids in aprotic medium, Electrochim. Acta 52 (2007) 2461-2470. [25] M. Salas-Reyes, J. Hernández, Z. Domínguez, F. González, P. D. Astudillo, R. E. Navarro, E. Martínez-Benavidez, C. Velázquez-Contreras, S. Cruz-Sánchez, Electrochemical oxidation of caffeic and ferulic acid derivatives in aprotic medium, J. Braz. Chem. Soc. 22 (2011) 693-701. [26] M. Font, E. Ardaiz, L. Cordeu, E. Cubedo, J. García-Foncillas, C. Sanmartin, J.A. Palop, Structural characteristics of novel symmetrical diaryl derivatives with nitrogenated functions. Requirements for cytotoxic activity, Bioorg. Med. Chem. 14 (2006) 1942. [27] A.A. Reinke, J.E. Gestwicki, Structure-activity relationships of amyloid betaaggregation inhibitors based on curcumin: influence of linker length and flexibility, Chem. Biol. Drug Des. 70 (2007) 206. [28] A. Sánchez, R.C. Guillén-Villar, R. Sánchez, R. Vargas, J. Garza, M.H. Matus, M. Salas-Reyes, Z. Domínguez, Electrochemical oxidation of symmetrical amides of ferulic acid in aprotic medium, Electrochim. Acta 133 (2014) 546–554. [29] A. Sánchez, O. Martínez-Mora, E. Martínez-Benavidez, J. Hernández, Z. Domínguez, M. Salas-Reyes, Electrochemical behaviour of new dimeric esters and amides derived from caffeic acid in dimethylsulfoxide, Org. Biomol. Chem. 12 (2014) 5981–5989. [30] S. Schwaiger, R. Cervellati, C. Seger, E.P. Ellmerer, N. About, I. Renimel, C. Godenir, P. André, F. Gafner, H. Stuppner, Leontopodic acid ‒ a novel highly substituted glucaric acid derivative from Edelweiss (Leontopodium alpinum Cass.) and its antioxidative and DNA protecting properties, Tetrahedron 61 (2005) 46214630. [31] M.H. Matus, Z. Domínguez, M. Salas-Reyes, J. Hernández, S. Cruz-Sánchez, Conformational study of caffeic acid derivatives, J. Mol. Struct.: THEOCHEM 953 (2010) 175-181. [32] J.L. Gázquez, A. Cedillo, A. Vela, Electrodonating and electroaccepting powers, J. Chem. Phys. A 111 (2007) 1966-1970. [33] S. Son, E.B. Lobkowsky, B.A. Lewis, Caffeic acid phenethyl ester (CAPE): Synthesis and X-ray crystallographic analysis, Chem. Pharm. Bull. 49 (2001) 236238. [34] I.S Ufimtsev, T.J. Martinez, Quantum chemistry on graphical processing units. 3. Analytical energy gradients, geometry optimization, and first principles molecular dynamics, J. Chem. Theory Comput. 5 (2009) 2619-2628. 22

[35] C. Adamo, C. Barone, Toward reliable density functional methods without adjustable parameters: The PBE0 model, J. Chem. Phys. 110 (1999) 6158-6170. [36] R. Krishnan, J.S. Binkley, J.A. Pople, Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions, J. Chem. Phys. 72 (1980) 650-654. [37] Gaussian 09, Revision D.01, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Jr. Montgomery, J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, M.J. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, Ö. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian, Inc., Wallingford CT, 2009. [38] A.V. Marenich, C.J. Cramer, D.G. Truhlar, Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions, J. Phys. Chem. B 113 (2009) 6378-6396. [39] D.P. Astudillo, J. Tiburcio, F.J. González, The role of acids and bases on the electrochemical oxidation of hydroquinone: Hydrogen bonding interactions in acetonitrile, J. Electroanal. Chem. 604 (2007) 57-64. [40] A.J. Bard, L.R. Faulkner, Electrochemical methods, fundamentals and applications, Wiley & Sons, New York, 2001 (Chapters 5 and 9). [41] D.P. Valencia, F.J. González, Estimation of diffusion coefficients by using linear correlation between the diffusion coefficient and molecular weight, J. Electroanal. Chem. 681 (2012) 121-126. [42] D.R. Dimmel, L.F. Perry, P.D. Palasz, H.L. Chum, Electron transfer reactions in pulping systems (II): Electrochemistry of antraquinone/lignin model quinomethides, IPC, Technical paper series 141 (1984) 1. [43] J.A. Richards, D.H. Evans, Electrochemical oxidation of 2,6-di-tertr-butyl-4isopropylphenol, J. Electroanal. Chem. 81 (1977) 171-187. [44] J.R. Lenhard, R.W. Murray, Chemically modified electrodes. 13. Monolayer/multilayer coverage, decay kinetics, and solvent and interaction effects for ferrocenes covalently linked to platinum electrodes, J. Am. Chem Soc. 100, (1978) 7870-7875. [45] P.D. Astudillo, A. Galano, F.J. González, Radical grafting of carbon surfaces with alkylic groups by mediated oxidation of carboxylates J. Electroanal. Chem. 610 (2007) 137-146. [46] V. Budavári, Á. Szűcs, Cs. Somlai, M. Novák, Noncovalently bonded quinone on self-assembled molecular layers, Electrochimica Acta 47 (2002) 4351-4356. [47] G.A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press, New York, 1997. 23

[48] R. F. W. Bader, Atoms in molecules: A quantum theory, Oxford University Press: New York, (1990). [49] R. Hernández-Esparza, S.-M. Mejía-Chica, A.D. Zapata-Escobar, A. GuevaraGarcía, A. Martínez-Melchor, J.-M. Hernández-Pérez, R. Vargas, J. Garza, J. Comput. Chem. In press. [50] L.I. Perea-Ramírez, B.S. Thesis, Universidad Veracruzana, Campus Xalapa, México, 2012.

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CAPTIONS TO FIGURES Figure 1. Caffeic acid (CA), sinapic acid (SA), and ferulic acid (FA). Figure 2. Covalent diferulates cross-linked between polysaccharides found in plant tissues (1), diesters derived from FA identified in natural products (2-5) and curcumine (6) Figure 3. FA esters derivatives studied in the present work. Figure 4. Cyclic voltammetry in acetonitrile + 0.1 M n-Bu4NPF6, on glassy carbon electrode (3 mm φ) at 0.1 V s-1 of compound 7 (1mM), 8 and 10 (2 mM). Figure 5. Successive cyclic voltammetry of the oxidation of: A) compound 7 and B) compound 8; in acetonitrile + 0.1 M n-Bu4NPF6 on glassy carbon electrode (3 mm φ) at 0.1 V s-1. Figure 6. Cyclic voltammetry in acetonitrile + 0.1 M n-Bu4NPF6, on glassy carbon electrode (3 mm φ) at 0.1 V s-1 of 9: A) cycles 1-4 (voltammograms a-d) and B) cyclic voltammetry to cathodic direction after four cycles. Figure 7. Cyclic voltammetry in acetonitrile + 0.1 M n-Bu4NPF6, on glassy carbon electrode (3 mm φ) at 0.1 V s-1 of 11 at 2 mM. Figure 8. A) Cyclic voltammetry of compound 11 at 2 mM in acetonitrile + 0.1 M nBu4NPF6, at 0.1 V s−1 and switching potential (Eλ) =1.29 V/SCE on glassy carbon electrode (3 mm φ); B) cycle 2, obtained at the last solution composition and by bubbling the working solution; and C) cyclic voltammetry to cathodic direction of the resulting pasived electrode in a solution containing only acetonitrile + 0.1 M nBu4NPF6. Figure 9. Optimized structures for A) FA and B) compound 10 at the PBE0/6311G** level of calculation.

25

Figure 10. Optimized structures for compound 7 at the PBE0/6-311G** level of calculation: A) lowest energy structure found in this work, compound 7-1; B) compound 7-2, ∆Erel = 1.05 kcal/mol; C) front view and lateral view of compound 73, ∆Erel = 1.06 kcal/mol; D) compound 7-4, ∆Erel = 1.95 kcal/mol; and E) compound 7-5, ∆Erel = 2.43 kcal/mol. Figure 11. Optimized structure for compound 11 at the PBE0/6-311G** level of calculation: A) front view and B) lateral view showing the interactions that may produce the folding of the structure (a = 2.79 Å, b = 2.56 Å, and c = 2.54 Å). Figure 12. AIM analysis for compound 11. The small spheres represent points where the gradient of the electron density is cancelled (critical points) and the lines connect these points with the corresponding attractors (nuclei). Scheme 1. ECE mechanism. Scheme 2. Representation of neutral radical generated during the oxidation of mechanism of FA derivatives (I) and structure proposed for modified GCE (II) after reaction with I.

26

Table 1. Comparison between theoretical AIP, VIP, ω− (calculated with AN as solvent) and experimental OP for FA and compounds 7, 10, and 11.

Theoretical parameters

FA

10

7

11

Adiabatic ionization potential, AIP (eV)

5.64

5.60

5.41

5.43

Vertical ionization potential, VIP (eV)

5.72

5.69

5.46

5.47

Electrodonating power, ω− (eV)

7.28

7.17

7.75

7.96

FA

10

7

11

1.16

1.22

1.27

1.53

Experimental parameters Oxidation potential, OP (V vs SCE)

Table 1. Comparison between theoretical AIP, VIP, ω− (calculated with AN as solvent) and experimental OP for FA and compounds 7, 10, and 11.

Theoretical parameters

FA

10

7

11

Adiabatic ionization potential, AIP (eV)

5.64

5.60

5.41

5.43

Vertical ionization potential, VIP (eV)

5.72

5.69

5.46

5.47

Electrodonating power, ω− (eV)

7.28

7.17

7.75

7.96

FA

10

7

11

1.16

1.22

1.27

1.53

Experimental parameters Oxidation potential, OP (V vs SCE)

27

Electrochemical oxidation of two dimeric and one tripodal ferulic acid esters

Molecular topology has an effect on electrochemical behaviour of Ferulic Acid esters

Electrodonating power values were compared with experimental oxidation potentials

28